Project Summary Genome wide association studies (GWAS)-based pharmacogenomics is a robust, unbiased, non- hypothesis driven approach that interrogates the whole genome for the presence of common genetic variants or single nucleotide polymorphisms (SNPs) associated with differential drug responses. Clinical use of genetic information to guide decisions requires only that the genetic association is sufficiently robust to be predictive in the clinical setting; the biological or functional consequences of the genetic variation need not be known. However, in most successful examples of disease genetics or pharmacogenomics where there is a clinical application, the functional mechanism of the genetic association is understood. Such information is particularly important for understanding mechanisms underlying differential drug responses, and ultimately may facilitate identification of new drug targets, both of which are additional goals of pharmacogenomics studies. Thus, in order to fully exploit available pharmacogenomics findings, it is imperative to perform molecular studies of the associated variants in the appropriate tissues of relevance for the phenotype of interest. Animal models have been utilized extensively for studying systemic diseases; however, they are not useful for understanding the biological impact of human genetic variants. Therefore a novel approach for studying human cells and tissues is needed. Human induced pluripotent stem cells (iPSCs) have been implicated for the study of mechanisms underlying how single nucleotide polymorphism (SNP) variations affect drug responses. However, no systematic approach has been applied to the field due to limited available resources as well as technical barriers. Here we propose to establish a Pharmacogenomics iPSC Library and Service (PiLS) resource. This resource will encompass a rationally sized iPSC library with an integrated SNP database, providing practical and accessible methods for many investigators to study potential impacts of SNPs on drug responses quickly and easily. Since the effects of each SNP variant can often be minor and/or subtle, we postulate that it is extremely important to utilize isogenic cells to decode the significance of each identified gene variant. Aim 1 will establish a library of iPSCs using a stock of peripheral blood mononuclear cells derived from healthy control individuals that have undergone genome-wide SNP genotyping. We aim to generate iPSC clones from 50 individuals, expecting to obtain approximately 5 independent individual iPSC lines heterozygous for any given SNP with 5% minor allele frequency (MAF). Aim 2 will establish two practical SNP targeting and editing approaches using such SNP-heterozygous iPSCs from the library. The system we develop here is robust, straightforward, and easily applicable to studies of various SNP variants, which will have a great impact on advancing pharmacogenomics. Ultimately, we will provide not only biological and molecular resources but also an integrated protocol and support system designed to ensure that this initial investment provides returns for years to come. We believe that the present resource will be widely welcomed in the pharmacogenomics community.